Coffee is by far the most widely and highly consumed herbal extract. Numerous epidemiological studies indicate that coffee consumption affords reduced risk of Parkinson's disease (PD). This association has been attributed to caffeine, but coffee is much more than just caffeine, and the finding that caffeine may be neuroprotective in no way obviates the possibility that other components in coffee may play a synergistic role with caffeine. We have recently isolated a lipid-like component of coffee, eicosanoyl-5-hydroxytryptamide (EHT), and found it to have a protective effect in mouse models of PD. Biochemical and neuropathological analyses demonstrate that dietary supplementation with EHT leads to decreased 1-synuclein phosphorylation and aggregation, a robust anti-inflammatory effect, and protection against oxidative stress. Studies indicate that the actions of caffeine stem from its antagonism of adenosine A2A receptor signaling, but downstream neuroprotective mechanisms remain to be established. The proposed research will elucidate the molecular mechanisms of neuroprotection mediated by caffeine and EHT as well as their synergy through in vitro biochemical analyses, cell based molecular experiments and in vivo studies in mouse models of PD. The ultimate goal of this work is to develop a dietary supplement(s) or medical food that would slow the progression or prevent the development of neurodegenerative disorders such as PD.